tbuckley/cabot-search huggingface dataset:
DDDR-37. GB5121 IS A NOVEL, IRREVERSIBLE, COVALENT BTK INHIBITOR WITH HIGH SELECTIVITY AND CNS-PENETRANCE FOR TREATMENT OF CNS MALIGNANCIES
Authors: Isharat Yusuf, David Guimond, Zachary Naiman, Theodore Schiff, Bryan Clemons, Bryanna Paulson, Kay Hou, Kristen Taylor Meadows, Mark Rose, Laura Carter
Journal: Neuro-Oncology (2022)

Abstract Inhibitors of Bruton’s tyrosine kinase (BTK) are approved treatments for several B cell lymphomas. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) exposure which is important in instances of CNS disease. GB5121 is an orally available, selective, irreversible, covalent small molecule BTK inhibitor that was designed to address these limitations. Here, GB5121 was profiled for selectivity, potency, inactivation kinetics and CNS penetrance in comparison to ibrutinib. GB5121 pharmacodynamic properties were evaluated using both cell-free enzymatic and cell-based functional assays, showing nM potency for BTK inhibition and rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissue, a critical parameter for irreversible inhibitors. In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating &amp;gt; 50% inhibition at 1 µM; GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. When compared with other BTK inhibitors, GB5121 showed superior CNS target occupancy using a probe-based ELISA measuring free BTK in the brain of mice receiving 3 daily oral doses. GB5121 also demonstrated significantly higher brain to plasma ratio in mice with an intact blood brain barrier. In non-human primates, a 1:1 brain to plasma concentration ratio was demonstrated for GB5121 for up to 8 hours with both oral (30 mg/kg) and IV (2 mg/kg) doses. Together, these features differentiate GB5121 from both FDA-approved BTK inhibitors, as well as those currently under clinical investigation. Our data supports the use of GB5121 in clinical trials where BTK is a known driver of malignancies, including CNS lymphoma. This research has been previously presented at the AACR Annual Meeting 2022.
NIMG-63. PRE-SURGICAL RADIO-PATHOMIC MAPS OF TUMOR CELLULARITY PREDICT EARLY RECURRENCE IN GLIOBLASTOMA PATIENTS
Authors: Aleksandra Winiarz, Samuel Bobholz, Allison Lowman, Savannah Duenweg, Fitzgerald Kyereme, Dylan Coss, Elizabeth Cochran, Jennifer Connelly, Peter LaViolette
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Glioblastoma time to recurrence following initial surgery is difficult to predict as it differs widely between patients. This is important as those who recur early have a poorer prognosis and shorter survival time. This study aimed to test the hypothesis that cell density, as defined by a predictive radio-pathomic mapping model, would indicate a more aggressive tumor, and thus carry a lower time to progression. METHODS 18 confirmed glioblastoma patients were included in this study. All patients underwent surgery followed by chemo-radiation, consistent with standard of care. Inclusion criteria also included radiographic recurrence, and autopsy confirmation of recurrent glioblastoma. Three magnetic resonance imaging (MRI) timepoints were investigated: pre- and post-surgery, and tumor recurrence defined by a radiologist. Patients were classified into two groups, early recurrence, as defined by tumor progression in the first 6 months post-surgery MRI (n=9, average 116 days to recurrence), and late recurrence, which included everyone else (n=9, average 283 days to recurrence). Contrast enhancement and FLAIR hyperintensity regions of interest were annotated from the patients’ T1+C and FLAIR scans. Radio-pathomic maps of predicted tumor cellularity were generated from a previously published machine learning model trained to identify tumor pathology using aligned autopsy tissue samples as ground truth to clinical MRI scans. The T1, T1+C, FLAIR, and apparent diffusion coefficient (ADC) images were used as input. Tumor cellularity values were then averaged across the T1+C and FLAIR ROIs. RESULTS Both pre- and post-surgical cell density within contrast enhancement was significantly greater in patients with early recurrence compared to those who recurred later (p ≤0.05). CONCLUSIONS Our results suggest that radio-pathomic maps of cell density can identify early-recurrence in patients prior to treatment. This may help with treatment planning for radiologists, surgeons, and neuro-oncologists which may include more aggressive surgery and more frequent monitoring.
INNV-18. PROLONGED REMISSION AFTER TREATMENT WITH SINGLE-AGENT IBRUTINIB AS MAINTENANCE THERAPY FOLLOWING SALVAGE RADIATION THERAPY FOR REFRACTORY/RELAPSE PRIMARY CNS LYMPHOMA
Authors: Steven Du, Daniela Bota, Xiao-Tang Kong
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease. Standard induction therapy for PCNSL consists of a high-dose methotrexate-based (HD-MTX) regimen. For relapsed or refractory primary CNS lymphoma (r/r PCNSL), most of the non-standard treatment regimens including additional chemotherapy, stem cell transplant, or whole brain radiation therapy (WBRT) may not reach long-term remission due to intolerance of the treatment by the patients or lack of effects. Here we report a case with r/r PCNSL reached more than 50-month remission after salvage WBRT followed by single agent ibrutinib maintenance therapy. CASE REPORT: a 75-year-old female with PCNSL, experienced disease recurrence, despite undergoing multiple lines of treatment including initial HD-MTX, second-line rituximab and temozolomide, repeated HD-MTX, and a clinical trial. Because her disease was refractory to these treatment options, we decided to start WBRT as salvage therapy, which resulted in significant reduction of tumor burden. Prior studies, however, showed that r/r PCNSL patients who underwent salvage WBRT alone had a median survival of only 1-2 years. Therefore, to extend the remission after salvage WBRT, she opted to try ibrutinib, a Bruton’s tyrosine kinase inhibitor with past success in treating r/r PCNSL patients, as maintenance therapy after salvage WBRT. She tolerated well and decided to be off the treatment after 18 month-maintenance therapy. The patient has been stable clinically. She has since survived for more than 50 months after the completion of salvage WBRT plus maintenance therapy with ibrutinib. DISCUSSION Compared to prior reports of 11 to 16 months of median survival after salvage WBRT alone for r/r PCNSL, our case has had prolonged survival, which supports the potential positive effect of ibrutinib as maintenance therapy for r/r PCNSL after salvage WBRT
EXTH-87. DECITABINE POTENTIATES MENINGIOMA IMMUNOTHERAPY TARGETING NY-ESO-1
Authors: Matthew Sun, Joey Orpilla, Erick Contreras, Marisa Imbroane, Janet Treger, Anthony Wang, MyungJun Ko, Jeremie Vitte, Marco Giovannini, Linda M Liau, Robert Prins, Richard G Everson
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION No immunotherapy exists for meningiomas. NY-ESO-1 is a potential target because in meningiomas it’s the most frequently expressed Cancer-Testis-antigen. Decitabine is a hypomethylating agent known to upregulate CT-antigens. We tested the effects of decitabine on NY-ESO-1 expression in primary and immortalized meningioma cultures, and its impact on the efficacy of NY-ESO-1 T-cell-receptor-transduced T-cells(TCRs), to understand its potential role in meningiomas immunotherapy. METHODS We established primary meningiomas cultures from fresh tumor specimens and quantified NY-ESO-1 expression using Western blot and qRT-PCR. Cultures were pre-treated with 1uM of decitabine for at least 48 hours before assays. In vitro cytolysis was measured using the xCelligence Real-Time Cell Analyzer System in meningioma co-cultures with MHC-Class-I(HLA-A*0201)–restricted NY-ESO-1(157 – 165)-specific TCRs. RESULTS Nine primary and three immortalized meningioma cultures(Grade I – III) were evaluated for baseline NY-ESO-1 expression. High expression was defined as &amp;gt; 100-fold overexpression compared to glioma(U251) cultures. Decitabine treatment significantly increased NY-ESO-1 expression in 6 primary and 2 immortalized(SF1335, grade 1; IOMM-LEE, grade 3) cultures with low baseline expression(median increase over 100 fold; p &amp;gt; 0.001); whereas it slightly decreased NY-ESO-1 expression in 3 primary and 1 immortalized culture(CH157, WHO grade 3) with high baseline expression(median decrease 20%;p&amp;lt; 0.001). Decitabine pre-treatment of meningioma before co-culture with NY-ESO-1 TCRs at a ratio of 1:1, increased tumor cytolysis for SF1335, from 20% to 40%, and for IOMM-LEE, from 0% to 85%, measured at 10 hours. NY-ESO-1 expression increased 5000-fold vs 10-fold for IOMM-LEE vs SF1335, respectively. Decitabine treatment also increased MHC-Class-I expression for IOMM-LEE but not SF1335. Decitabine pre-treatment did not change cytolysis of CH157 at 65%(10 hrs). CONCLUSIONS Decitabine upregulates NY-ESO-1 expression in meningiomas with low baseline expression, and it increases cytolytic effects of NY-ESO-1 TCRs proportional to NY-ESO-1 and MHC-Class-I molecule upregulation. Decitabine may be a clinically feasible adjunct to meningioma immunotherapy.
CSIG-19. THE PI3K/AKT/MTOR SIGNALING CASCADE MAY CONTRIBUTE TO SEX DIFFERENCES IN GLIOBLASTOMA
Authors: Jasmin Sponagel, Hannah Johnston, Hannah Gass, Elena Nunez, Joseph Ippolito, Joshua Rubin
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients exhibit a survival advantage. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. The PI3K/Akt/mTOR signaling cascade plays a crucial role in GBM development and progression as it is involved in the regulation of cellular growth, survival, nutrient sensing, and metabolic activity. To investigate whether the PI3K/Akt/mTOR signaling cascade may differ in male and female GBM patients, we first assessed survival data of male and female GBM patients using the TCGA RPPA phosphoproteome data set and found that changes in protein phosphorylation of components of the PI3K/Akt/mTOR pathway, including mTOR phosphorylation, worsen the outcome of male but not female GBM patients in a dose-dependent fashion. This was supported by in vitro experiments of murine transformed astrocytes where pathway stimulation via treatment with insulin, IGF-1, or EGF significantly increased pathway activity in male but not female cells. Furthermore, pathway inhibition via serum deprivation resulted in a significant decrease in pathway activity in male but not female cells, indicating that male transformed astrocytes exhibit higher sensitivity to inhibitory conditions (serum deprivation) and stimulatory conditions (insulin, IGF-1, or EGF treatment). Together, these data suggest that (i) the PI3K/Akt/mTOR pathway activity may affect male and female GBM outcome differently, and (ii) there are sex differences in the regulation of the PI3K/Akt/mTOR signaling cascade in GBM which may contribute to the sex disparity in GBM. Our data add to the growing body of literature regarding the presence of sex differences in PI3K/Akt/mTOR signaling in health and disease and provide important insight for the development of translatable approaches to treatment for male and female GBM patients.
STEM-17. IDENTIFICATION OF LOMERIZINE, A PROPHYLACTIC DRUG FOR MIGRAINES, AS A POTENTIAL ANTI-GLIOBLASTOMA DRUG
Authors: Toshiya Ichinose, Sho Tamai, Hemragul Sabit, Shingo Tanaka, Masashi Kinoshita, Mitsutoshi Nakada
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma (GBM) is one of the most malignant primary brain tumors. Despite development of treatment, prognosis of GBM is still poor. Here, we identified lomerizine, a prophylactic drug for migraine, as a potential anti-GBM drug from thousands of existing compounds. We investigated its therapeutic effects both in vitro and in vivo with the purpose of drug repositioning. Materials and method: Human patient-derived glioma stem cell line (KGS01, KGS10, KGS15), their differentiated cells, and GBM cell lines (A172, SNB19, T98, U87) were used. Proliferation assay, migration assay, invasion assay and sphere-forming assay were performed. We analyzed various signaling pathways altered by lomerizine by Western blotting. In addition, induction of apoptosis was evaluated by immunofluorescence and Annexin V assay. Anti-GBM effects of lomerizine in vivo with a mouse brain tumor model was validated Result: Lomerizine inhibited proliferation, migration, and invasion dose-dependently in all cell lines, especially in GSCs. Sphere formation was inhibited by lomerizine in all GSCs. STAT3, which is involved in tumorigenesis, was dephosphorylated after the treatment with lomerizine in a dose-dependent manner in all cell lines. Furthermore, lomerizine induced apoptosis in both immunofluorescence and Annexin V assay. In vivo experiments showed a significant tumor suppression and prolongation of overall survival in the group of mice treated with lomerizine. CONCLUSION Lomerizine has anti-GBM effects.
NIMG-15. INTEGRATED RADIOGRAPHIC AND PATHOLOGICAL ANALYSIS OF MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNSTS) REVEALS IMAGING CORRELATES OF MOLECULAR ALTERATIONS AND CLINICAL OUTCOME
Authors: Devan Diwanji, Stephanie Texiera, Calixto-Hope Lucas, Evan Calabrese, Alyssa Reddy, Melike Pekmezci, Line Jacques, Cynthia Chin, Harish Vasudevan
Journal: Neuro-Oncology (2022)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in patients with neurofibromatosis type 1 (NF-1) yet non-invasive diagnosis and risk stratification of NF-1-associated peripheral nerve tumors remains challenging. Moreover, the relationship between radiographic features and pathologic measures such as mitotic index and necrosis, or molecular markers of malignant transformation such as H3K27 trimethylation and Schwann cell marker (S100B, SOX10) expression remain unknown. Here, we integrate positron emission tomography (PET) (n=32 studies from 18 patients) and magnetic resonance imaging (MRI) (n=20 studies from 20 patients) with immunohistochemical analysis and clinical follow-up in a total of 20 patients with pathologically confirmed MPNST diagnosis. The median age was 33 years (range 5-74 years), n = 11 were male (55%) and n=13 (65%) harbored a clinical diagnosis of NF-1. Anatomically, n=6 (30%) tumors arose near the spine, n=5 (25%) arose in the extremities, and n=4 (20%) arose in the sacrum. By PET, the average preoperative SUVmax was 8.53 with a trend toward increased SUVmax in Ki-67 high tumors (SUVmax 10.58 vs. 6.47, p=0.08). No significant differences in SUVmax based on H3K27 trimethylation, SOX10, or S100B expression was noted. The appearance of cystic necrosis by MRI was significantly associated with H3K27 trimethylation loss (Chi-square p=0.04) with a trend toward increased KI-67 labeling (43% vs. 24%, p = 0.07), suggesting cystic necrosis identifies aggressive lesions. No other features were correlated with H3K27 trimethylation status or Ki-67 labeling index. With regard to clinical outcome, dichotomized SUVmax identified patient subgroups with significant differences in overall survival (OS), with high SUVmax tumors demonstrating improved survival (median OS: 250 months vs. 60 months, log-rank test p=0.02). Our data support a relationship between radiographic features, histopathologic characteristics and clinical outcomes. Future work will include longitudinal analysis, validation in larger, multi-institutional cohorts and incorporation of radiomic approaches.
RADT-08. DOSIMETRIC FEASIBILITY OF DIRECT POST-OPERATIVE MRI-LINAC-BASED STEREOTACTIC RADIOSURGERY FOR RESECTION CAVITIES OF BRAIN METASTASES
Authors: M Sierts, E Seravalli, E Brand, M Maspero, S David, M E P Philippens, E H J Voormolen, J J C Verhoeff
Journal: Neuro-Oncology (2022)

Abstract Background Post-operative stereotactic radiosurgery (SRS) of patients with brain metastases with single resection cavities is typically planned on a post-recovery MRI, 4-6 weeks after resection. However, meanwhile the intracranial metastasis may (re-)grow, and postponing adjuvant systemic treatment increases chance on extracranial progression as well. Anticipating direct post-operative SRS to minimize this interval would enable rapid start of systemic therapy. In this study, we considered treatment with MRI-Linac (MRL) SRS, because of the possibility to execute the post-operative MRI and SRS treatment combined on the MRL instead of on two separate systems, improving logistics and increasing patient comfort. However, it is unclear whether MRL-based SRS may be feasible from a dosimetric perspective. This study aims to shed light on the dosimetric feasibility of MRL-based SRS. METHODS We simulated MRL treatments including thirteen patients with resectable single brain metastases treated with single fraction CT-Linac (CTL) SRS. We therefore contoured direct post-operative gross tumor volumes (GTV) and compared them to post-recovery MRI GTV. Next, we compared a non-coplanar VMAT technique for CTL (ncVMAT) to a coplanar IMRT technique for MRL (cIMRT), creating three plans per patient: a ncVMAT plan and a cIMRT plan for the direct post-operative GTV, and a post-recovery ncVMAT plan as current clinical standard. RESULTSCompared to GTVs defined on direct post-operative MRI, on post-recovery MRI 15.5% of cavities shrunk by &amp;gt; 2cc, and 46% expanded by &amp;gt; 2cc. Although direct post-operative ncVMAT plans had lower median gradient index and higher median V3Gy of the skin, they were clinically acceptable according to clinical guidelines. CONCLUSION Although slightly inferior to non-coplanar CTL plans, direct post-operative MRL-based SRS for resection cavities of brain metastases is dosimetrically acceptable, at the trade-off between increased patient comfort and logistics. Additionally, MRL-based SRS enables substantially earlier start with adjuvant systemic therapies, thereby maximizing tumor control.
EXTH-103. DISCOVERY AND PHARMACOLOGICAL CHARACTERIZATION OF SKL27969, A NOVEL BRAIN-PENETRATING PRMT5 INHIBITOR WITH STRONG ANTITUMOR ACTIVITY, IN GLIOBLASTOMA AND BRAIN METASTASIS PRECLINICAL MODELS
Authors: Mijin Moon, Yongje Shin, Ho Yeon Lee, Beomjin Hong, Jinhee Kim, Jun Lee, Janice K Laramy, Vijaykumar Vashi, Sook-Kyung Park
Journal: Neuro-Oncology (2022)

Abstract Protein arginine methyltransferase 5 (PRMT5), a type II methyltransferase, regulates cellular processes such as survival, proliferation, and apoptosis by inducing symmetric arginine dimethylation of multiple cellular proteins involved in the regulation of cellular transcription and RNA splicing. Elevated tumor PRMT5 protein level has recently been correlated with poor prognosis and poor patient survival in various human cancers, including glioblastoma multiforme (GBM), lung cancer, breast cancer, and ovarian cancer. SKL27969 is a highly selective and potent PRMT5 inhibitor that is designed for brain penetration. It strongly binds to S-adenosylmethionine (SAM)-bound PRMT5/MEP50 (methylosome protein 50), leading to potent cellular symmetric dimethylarginine (SDMA) inhibition with an IC50 of 3.4 nM. Cell line panel profiling of SKL27969 revealed a broad spectrum of anti-proliferative activity in various cancer cell types, including CNS tumors, solid cancers prone to spread to brain, other solid cancers, and hematologic cancers. SKL27969 showed excellent brain exposure, with total and unbound partition coefficient (Kp and Kpuu) values of 6.57 and 1.08, respectively, and high tumor-to-plasma ratio, which resulted in significant survival benefit in orthotopic GBM xenograft models and metastatic brain cancer models such as intracranial xenograft models of non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC). Administration of SKL27969 showed strong tumor growth suppression in subcutaneous xenograft models of GBM, NSCLC, or TNBC. High correlation between tumor and plasma SDMA levels after SKL27969 treatment were observed in the preclinical models. Furthermore, SKL27969 showed potentiation of DNA damage when used in combination with DNA-damaging agents, which may suggest possible benefit as a combination therapy. Given the therapeutic target potential of PRMT5 in glioblastoma and other brain metastatic cancers, and the preclinical efficacy of SKL27969, these results have enabled the initiation of Phase 1/2 open-label, multicenter dose-finding study in patients with advanced solid tumors (NCT05388435).
TMIC-26. USING INTEGRATED MULTIDIMENSIONAL MASS CYTOMETRY AND MULTIPLEX IMMUNOHISTOCHEMISTRY TO INFER SPATIAL RELATIONSHIPS BETWEEN PHENOTYPICALLY DISTINCT GLIOBLASTOMA INFILTRATING IMMUNE CELLS
Authors: Todd Bartkowiak, Asa Brockman, Sierra Lima, Madeline Hayes, Caroline Roe, Justine Sinnaeve, Akshitkumar Mistry, Nalin Leelatian, Bret Mobley, Lola Chambless, Reid Thompson, Kyle Weaver, Jonathan Irish, Rebecca Ihrie
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas (GBM) account for ~60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit; however, no predictive immune features have informed therapeutic stratification. Radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse prognosis compared to patients with ventricle non-contacting GBM (NC-GBM), yet the influence of ventricle contact on anti-tumor immunity is unknown. This study characterized the GBM immune microenvironment and identified targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM patients.Primary glioblastoma tissue was provided with written informed consent in accordance with the Declaration of Helsinki and with approval of the Vanderbilt Institutional Review Board (IRB #131870). Seventeen patients presented with primary, IDH-wildtype C-GBM and 15 with NC-GBM. Machine learning integrated mass cytometry and matched multiplex immunohistochemistry on FFPE embedded tissue to identify phenotypic, functional, and spatial biomarkers correlating with patient outcome. C-GBM tumors were enriched in STAT3-driven CD32+CD44+HLA-DR+ monocyte-derived macrophages (MDM) compared to NC-GBM (19 ± 8% vs. 6 ± 2%; p&amp;lt; 0.001) and depleted in lymphocytes (2.9 ± 1% vs. 7.6 ± 2%; p&amp;lt; 0.001) and tissue-resident microglia (1.8 ± 0.3% vs. 7 ± 3%; p&amp;lt; 0.001). Exhausted T cells in C-GBM co-expressed checkpoint receptors PD-1 and TIGIT. K-means clustering identified 10 immunological niches in GBM. Macrophage-tumor niches were most common in C-GBM (17.93% of niches), followed by T cell-microglia-tumor niches (17.72%). Within NC-GBM niches, T cell-T cell interactions were more prevalent (log odds ratio = 0.90) and correlated with improved outcome.These findings suggest that factors within the periventricular space negatively influence the immune microenvironment within GBM tumors. Clinically targetable immune biomarkers were identified in C-GBM. Notably, radiologic assessment of lateral ventricle contact may guide clinical trial design for immunotherapies in neuro-oncology based on tumor proximity to the ventricle wall.